The purpose of this research is the development and application of useful computational methods for studying the hydration of protein and other molecules. No adequate methods exist at the present time and their development is essential to an understanding of the role of solvent in biological systems. The basis of the approach is the extension of the Monte Carlo method for dense liquids to the study of protein solvent systems. The immediate objective is the application of the method to a protein crystal system, triclinic hen egg white lysozyme, addressing such questions as: what is the "structure" of the water in this crystal? How much bound water is there, and how does this water differ from bulk water? What is the energy of hydration of the crystal? What is the energy distribution of the water molecules in the lysozyme crystal and how does this differ from the energy distribution in bulk water? Finally, we propose to calculate the structure factors from the electron density of the calculated water distribution, along with the protein molecule, and thereby recalculate the agreement factor (R factor). Upon completion of this first stage the Monte Carle method will be applied to other objectives concerned with the nature and function of solvent in biological systems. These include: 1) The elucidation of the role of solvent in substrate and inhibitor binding. The simulation studies will be applied to the energetics of inhibitor and substrate binding in the lysozyme system, in solution, and where applicable, in the triclinic crystal (where experimental X-ray data is available). 2) The role of solvent in stabilizing the native protein. Again lysozyme will be used as the prototype system and the hydration energy and solvent structure of an extended chain will be compared with these properties for the native protein in solution. 3) Mechanism of denaturation. Finally, the mechanism of protein denaturation by various denaturants, and especially the indentification of the sites at which the denaturants act will be investigated by the simulation technique.